Design and synthesis of conformationally constrained 3-(N-alkylamino)propylphosphonic acids as...
Transcript of Design and synthesis of conformationally constrained 3-(N-alkylamino)propylphosphonic acids as...
Bioorganic & Medicinal Chemistry Letters 14 (2004) 4861–4866
Design and synthesis of conformationally constrained3-(N-alkylamino)propylphosphonic acids as potent agonists
of sphingosine-1-phosphate (S1P) receptors
Lin Yan,a,* Jeffrey J. Hale,a Christopher L. Lynch,a,� Richard Budhu,a Amy Gentry,a
Sander G. Mills,a Richard Hajdu,b Carol Ann Keohane,b Mark J. Rosenbach,b
James A. Milligan,b Gan-Ju Shei,b Gary Chrebet,b James Bergstrom,b Deborah Card,b
Hugh Rosenb,� and Suzanne M. Mandalab
aDepartment of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USAbDepartment of Immunology and Rheumatology, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
Received 3 June 2004; accepted 21 July 2004
Available online 20 August 2004
Abstract—A series of conformationally constrained 3-(N-alkylamino)propylphosphonic acids were systematically synthesized andtheir activities as S1P receptor agonists were evaluated. Several pyrrolidine and cyclohexane analogs had S1P receptor profiles com-parable to the acyclic lead compound, 3-(N-tetradecylamino)propylphosphonic acid (3), lowered circulating lymphocytes in miceafter iv administration and were thus identified as being suitable for further investigations.� 2004 Elsevier Ltd. All rights reserved.
N POH
OOH
a b
3, R = -H, S1P1 IC50 = 3.0 nM4, R = -CH3, S1P1 IC50 = 16 nM
R c
d
OR
1, R = -H, FTY7202, R = -PO3H2, FTY720 phosphate
NH2
OH
FTY720 (1, Fig. 1) is a novel immunosuppressant thatprolongs the survival of organ allografts in animals; ithas progressed through the clinic and is currently inPhase III trials for the prevention of kidney transplantrejection.1 The mechanism of FTY720-mediatedimmunosuppression, while not being fully understood,appears to be different from those of existing immuno-suppressants. Recent studies have shown that FTY720is phosphorylated in vivo by sphingosine kinase and thatFTY720-phosphate (2) is a potent agonist of a family ofsphingosine-1-phosphate (S1P) G protein-coupledreceptors.2,3 The activation of S1P1 receptor by 2 ispresumably responsible for the observed immunosup-pressive efficacy due to the subsequent sequestration oflymphocytes into secondary lymphoid organs, whichreduces and/or inhibits infiltration of lymphocytes intograft sites and inflamed tissues.4
0960-894X/$ - see front matter � 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.07.049
* Corresponding author. Tel.: +1-732-594-5419; fax: +1-732-594-
2210; e-mail: [email protected]�Present address: Abbott Laboratories, Dept. R4N6, Bldg. AP-10,
Abbott Park, IL 6006-6101, USA.�Present address: The Scripps Research Institute, ICND-118, 10550 N.
Torry Pines Road, La Jolla, CA 92037, USA.
Previous studies from these laboratories5 have shownthat 3-(N-tetradecylamino)propylphosphonic acid (3) is
NH
POH
OOH
5, S1P1 IC50 = 0.2 nM
Figure 1. FTY720 (1), FTY720-phosphate (2), and analogs 3–5 are all
potent agonists of S1P receptors. The letters shown by structure 3
mark the positions that were identified for tethering using short alkyl
chains.
4862 L. Yan et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4861–4866
a potent agonist of S1P receptors and that the properincorporation of a phenyl ring into the long alkyl chainof this compound gives 5, which has 15-fold greateraffinity for S1P1 than does 3. N-Methylation of 3, giving4, results in a 5-fold loss of affinity for S1P1. To extendthe scope of this work, efforts were undertaken to sys-tematically synthesize analogs of 3 in which the nitrogenand a neighboring carbon atom or a pair of adjacentcarbons of this compound were tethered with short alkylchains, with the goal of identifying novel scaffolds forS1P receptor agonists. This paper describes the synthesisand evaluation of these conformationally constrainedamino phosphonic acids and amino a-hydroxyl phos-phonic acids.6 Scaffolds identified here as being suitablefor S1P receptor agonists were elaborated into analogsof 5 to determine whether S1P1 receptor affinity was en-hanced similarly to that observed on going from 3 to 5.
The syntheses of analogs of 3 in which the nitrogen andan adjacent carbon are linked are described in Scheme 1.To tether the nitrogen to Ca with a propyl chain, treat-ment of 6 with s-BuLi in the presence of TMEDA7 fol-lowed by tetradecyl bromide gave pyrrolidine 7.Removal of Boc followed by N-alkylation of the result-ing pyrrolidine with diethyl 3-bromopropylphosphonateand ester cleavage led to pyrrolidine 8. For the cor-responding piperidine analog 12, reduction of N-Boc-piperidine-2-carboxylic acid (9) followed by TPAPoxidation8 provided aldehyde 10. This was condensed
10
g,
13 14
B. N-Cb:
17
m, n
18
C. N-Cc: l, o
D. N-Cd:
NBn
TMS OCH3 NH
CO2CH3
n = 1 21an = 2 21b
p
22
k, lNBoc
O
n NBoc
n
P(O)(OEt)2
HO
6
a
7
A. N-Ca: b, NBoc
N n-C14H29
Boc
NBoc
CHO
NBoc
OH i, jNBoc
PO(OEt)2
9
e, fNBoc
CO2H
Scheme 1. Reagents and conditions: (a) s-BuLi, TMEDA, THF, �78�C, the3-bromopropylphosphonate, K2CO3, DMF, 100�C (32–100%, two steps); (d)
cat. TPAP, 4A molecular sieves, CH2Cl2, rt (68%); (g) n-C12H25P(Ph)3Br, n
(i) (COCl)2, DMSO, DIEA, CH2Cl2, �78 to 0 �C; (j) tetraethyl methylenediph
(l) n-C13H27CHO, DIEA, NaB(OAc)3H, CH2Cl2 (92%); (m) methyl acrylate,
40�C (64%); (o) DIBAL, CH2Cl2, �78 to �65�C (50%); (p) diethyl phosphite
of isomers.
with n-dodecylphosphorane and then hydrogenated tosupply 11. Piperidine 12 was then obtained using proce-dures analogous to those used to convert 7 to 8. To linkthe nitrogen and Cb, Swern oxidation of N-Boc-pyrroli-dinemethanol (13) followed by Horner–Emmons olefina-tion gave 14. This was hydrogenated and then treatedwith anhydrous HCl in EtOH to furnish 15. Reductiveamination of 15 with n-tetradecylaldehyde followed byester cleavage delivered pyrrolidine 16. Connecting thenitrogen atom and Cc with an ethylene chain, featuredthe use of 1,3-dipole cyclization chemistry.9 Reacting17 and methyl acrylate in the presence of catalytic TFAfollowed by hydrogenation gave 18. Reductive amina-tion and DIBAL-H reduction of the ester provided alde-hyde 19, which was coupled with diethyl phosphite underPudovik conditions10 followed by ester cleavage to give20.11 Tethering the nitrogen and Cd with ethyl and pro-pyl chains was accomplished starting from 21a and21b, respectively, and also featured the Pudovik reaction.
The syntheses of analogs in which a pair of adjacent car-bons are tethered are shown in Scheme 2. To connect Ca
and Cb with a propyl chain, formylation of 11 usings-BuLi in the presence of TMEDA12 gave 24 as a 2:3mixture of cis and trans isomers. The mixture could beenriched in the cis isomer (6:1 cis/trans) by treating itwith silica gel. Condensation of 24 with tetraethylmethylenediphosphonate provided a mixture of phos-phonate esters, which were readily separated by silica
h
11
b, c, d
, d
23
Nn-C14H29
n
PO3H2
HO
12
c, d
8
NBoc
n-C13H27N
n-C13H27
PO3H2
N
n-C14H29
PO3H2
h, k
15
NH
PO(OEt)2 NPO3H2
n-C14H27
l, d
16
19
p, d
20
Nn-C14H29
CHO
Nn-C14H29
HOPO3H2
n n-C14H29Br, �78�C to rt (11%); (b) 9:1 CH2Cl2/TFA, rt; (c) diethyl
TMSI, CH2Cl2, rt (55–83%); (e) BH3ÆTHF, THF, rt (100%); (f) NMO,
-BuLi, THF, �78�C to rt (100%); (h) H2, 10% Pd/C, EtOH, rt (97%);
osphonate, NaHMDS, THF, (95%, two steps); (k) HCl, EtOH (100%);
cat. TFA, CH2Cl2, 0 �C to rt (100%); (n) Pd/C, NHþ4 CHO�
2 , CH3OH,
, Et3N, 100�C (24–71%). All final analogs are racemic or equal mixtures
30
gB. Ca-Cd:
N
OCH3
31
N n-C14H29
CBz
h, i
32
N
P(O)(OEt2)2HO
n-C14H29
34
kC. Cb-Cc:
35
l
36
OOH
P(O)(OEt2)2
n = 1 38an = 2 38b
nD. Cb-Cd:
39
m, dO O
P(O)(OEt2)2n n
40a (1:1 mix of cis and trans)40b-cis
40b-trans
HN
PO3H2n
n-C14H29
13
e
27
f
28
11
aA. Ca-Cb:
N
24
N CHOBoc
b
25-cis25-trans
Nn-C13H27
Bocn-C13H27 P(O)(OEt2)2
NBoc
OHNBoc
HONOHC n-C14H29n-C14H29
n-C13H27
c, j
33
NH
PO3H2HO
n-C14H29
O
CBz
c, d
26-cis26-trans
NH
n-C13H27 PO3H2
b, c, d
29
NH
n-C14H29 PO3H2
Boc
Boc
m, d
37
O
P(O)(OEt2)2
HN
PO3H2
n-C14H29
Scheme 2. Reagents and conditions: (a) (1) s-BuLi, TMEDA, THF, �78 to �30�C, (2) DMF, �78�C (83%); (b) tetraethyl methylenediphosphonate,
NaN(TMS)2, THF, 0 �C to rt (67–85%); (c) H2, Pd/C, EtOH, rt (66–100%); (d) TMSBr, CH3CN, 70�C (44–100%); (e) (1) s-BuLi, TMEDA, THF,
�78�C, then n-C14H29Br, �78�C to rt (4–9%); (f) NMO, cat. TPAP, 4A molecular sieves, CH2Cl2, rt (60–77%); (g) (1) CBZ-Cl, THF, �23�C, (2)n-C14H29MgCl, THF, �23 to �16�C, (3) 10% HCl, rt (100%); (h) L-Selectride, THF, �20�C to rt (56%); (i) diethyl phosphite, Et3N, 100�C (15%);
(j) TMSI, CH2Cl2, rt; (k) n-BuLi, diethyl methylphosphonate, BF3ÆEt2O, THF, �78�C (100%); (l) (COCl)2, DMSO, Et3N, CH2Cl2, �78 to 0 �C(87%); (m) n-C14H29NH2, NaB(OAc)3H, CH2Cl2, rt (38%); (n) (1) diethyl phosphite, N,N-bis(trimethylsilyl)acetamide, TMSOTf, CH2Cl2, 0 �C to rt,
(2) 1.0N HCl, rt (70–91%). All final analogs are racemic or equal mixtures of isomers.
L. Yan et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4861–4866 4863
gel chromatography. The individual diastereomers, 25-cis and 25-trans, were hydrogenated then treated withiodotrimethylsilane to deliver the final piperidines, 26-cis and 26-trans. For the corresponding 2,5-trans pyrrol-idine analog 29, treatment of 13 with s-BuLi in thepresence of TMEDA followed by n-tetradecyl bromideled to 27.13 Alcohol 27 was oxidized to aldehyde 28,which was readily converted to pyrrolidine 29.14 Totether Ca and Cd, acylation of 4-methoxypyridine (30) withbenzyl chloroformate followed by alkylation with n-tet-radecylmagnesium chloride15 gave 1,2,3,4-tetrahydropy-ridine 31. Conjugate reduction of 31 with L-Selectridefollowed by a Pudovik reaction afforded a-hydroxylphosphonate 32, which was readily converted to piperi-dine 33. Epoxy ring opening of cyclohexene oxide (34)by diethyl methylphosphonate16 was the first step in aroute used to link Cb and Cc. Swern oxidation of alcohol35 followed by reductive amination and ester cleavageresulted in cyclohexane 37. To tether Cb and Cd, Mi-chael addition of diethyl phosphate to either cyclopente-none or cyclohexenone17 was featured in the synthesesof cyclopentane 40a (obtained as a mixture of cis andtrans isomers) and cyclohexanes 40b-cis and 40b-trans.
Three different scaffolds, exemplified by pyrrolidine 23,pyrrolidine 29 and cyclohexane 40b-trans, were amongthose found to be tolerated as scaffolds for S1P receptor
agonists, so analogs of these with a phenyl ring incorpo-rated into their long alkyl chains5 were prepared(Scheme 3). For the cis and trans analogs of 29,Friedel–Crafts acylation of 1-phenylnonane (38) withsuccinic anhydride followed by esterification of theresulting carboxylic acid gave a c-keto ester 43. The ke-tone carbonyl group was converted into an oxime,which was subsequently reduced and cyclized to furnishlactam 44. Treatment of 44 with Meerwein�s salt led toan imino ether, which was condensed with Meldrum�sacid to afford isopropylidene malonate adduct 45.18
Methanolysis of 45 provided an enamine ester, whichwas subsequently reduced by sodium cyanoborohydrideto give a separable 2:1 cis/trans mixture of b-amino es-ters 46. The relative stereochemistry of substituents onthe pyrrolidine rings were determined with NOE NMRexperiments. Reduction of 46-cis with LAH followed byN-Boc protection and TPAP oxidation delivered analdehyde, which was condensed with diethyl phosphiteto provide a-hydroxyl phosphonate 47. The hydroxylgroup was reduced using the Barton–McCombie proto-col;19 this was followed by global deprotection tofurnish 48-cis. 48-Trans was obtained analogously from46-trans. To stereospecifically prepare the analog ofcyclohexane 37, ketone 21b was reduced to 1,2-cisalcohol with L-Selectride. The hydroxyl group was con-verted to inverted amine 50 with in three steps; this was
21b
p
O
P(O)(OEt)2
49
OH
P(O)(OEt)2
50
NH2
P(O)(OEt)2
51
HN
PO3H2
q, r, s t, o
n-C9H19 OO O+a, b
NH
On-C9H19
c, d, e
NHn-C9H19
A.
41 42 44
45
B.
Nn-C9H19 BOC
47
f, g
j, k, l
NHn-C9H19
48-cis48-trans
PO3H2
n-C9H19
17
u, dN OCH3
52 53
t, o
C.
TMSBn
NH
P(O)(OEt)2
N
PO3H2
n-C9H19
P(O)(OEt)2
OH
NH
ArCO2CH3
H H
n.o.e.
46-cis
NHn-C9H19
46
CO2CH3
O
O
O
O
m, n, o
n-C9H19
OOCH3
O
43
h, i
NH
ArCO2CH3
H H
n.o.e.
46-trans
X
Scheme 3. Reagents and conditions: (a) AlCl3, CH2Cl2, 0 �C to rt; (b) CH3OH, toluene, c.H2SO4, 80�C (77%, two steps); (c) H2NOHÆHCl, NaOAc,
EtOH, reflux; (d) H2 (50psi), Pd/C, AcOH; (e) pyridine, 80�C (79–83%, three steps); (f) (CH3)3OÆBF4, CH2Cl2, rt; (g) Meldrum�s acid, Et3N, benzene,
reflux (35%, two steps); (h) NaOCH3, CH3OH, reflux (58–61%); (i) Na(CN)BH3, pH3–4, CH3OH, rt (96–99%); (j) (1) LAH, THF, rt, then (BOC)2O,
rt (65–86%); (k) cat. TPAP, NMO, CH2Cl2, 0 �C to rt (60–74%); (l) diethyl phosphite, NaHMDS, 0 �C to rt (63–100%); (m) NaH, CS2, imidazole,
CH3I, THF, 0 �C (39–41%); (n) Bu3 SnH, cat. AIBN, toluene, reflux (80–100%); (o) TMSBr, CH3CN, 65�C (66%); (p) L-Selectride, THF, �78�C(54%); (q) MsCl, DIEA, CH2Cl2, 0 �C (65%); (r) NaN3, DMF, 60�C (55%); (s) H2 (40psi), 10% Pd/C, EtOH (100%); (t) 4-nonylbenzaldehyde,
NaB(OAc)3H, CH2Cl2, rt (32%); (u) diethyl vinylphosphonate, cat. TFA, CH2Cl2, rt (100%). All final analogs are racemic or equal mixtures of
isomers.
4864 L. Yan et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4861–4866
followed by reductive amination and ester cleavage toprovide 51. For the des-hydroxy analog of pyrrolidine23, 1,3-dipole cyclization of diethyl vinylphosphonateand 17 was featured in the sequence that gave pyrrol-idine 53.
The S1P receptor binding affinities (IC50s) of test com-pounds were determined in competitive binding assayswith human S1P receptors transfected in Chinese ham-ster ovary (CHO) cell membranes using [33P]-labeledS1P as the ligand.2 Agonism of S1P receptors wasdetermined by measuring the uptake of [35S]-GTPcS bytransfected CHO cell membranes expressing S1P recep-tors. All compounds were found to be agonists of S1Preceptors while calculated IC50 and EC50 values weregenerally found to agree within a factor of 10 (only40b has a factor of 26). The binding affinities of leadcompounds 3 and 4 and those of the conformationallyconstrained analogs can be compared in Table 1. Thebinding affinities of all of the new analogs for S1P1,S1P3, and S1P5 receptors were significantly affected by
the tethering position, while most compounds had loweraffinities for S1P2 and S1P4. Three n-alkyl analogs thatmaintained the secondary amine group of 3, piperidine26-trans, pyrrolidine 29 and cyclohexane 40b-trans, werefound to have single digit nanomolar S1P1 affinitiescomparable to that of 3. Comparing the receptor datafor the diastereomers of piperidine 26 and cyclohexane40 indicates that the trans stereochemistry is preferredfor both of these scaffolds. Of the other scaffolds, pyrr-olidines 20 and 23a also appeared promising since theirS1P1 affinities were both found to be within a factor ofthree to that of tertiary amine 4. Unfortunately, noneof the new scaffolds appeared to offer advantages over3 or 4 regarding S1P receptor subtype selectivity.
From the new scaffolds, three were chosen for furtherinvestigation and analogs with a phenyl ring in theirlong alkyl chains were prepared. Pyrrolidine analogs48-cis and 48-trans and cyclohexane analog 51 were allfound to have greatly enhanced affinity for S1P1 as com-pared to their n-alkyl counterparts (Table 2). A similar
Table 2. Inhibition (IC50, nM) of [33P]-S1P binding to S1P receptorsa
and mouse peripheral lymphocyte loweringb (PLL) for selected analogs
Compound S1P1 S1P2 S1P3 S1P4 S1P5 PPL ED50
(mg/kg iv)
5 0.16 750 2.7 8.4 0.73 87% @ 0.25c
48-cis 0.10 422 2.8 31 0.58 89% @ 0.25c
48-trans 0.16 >1000 4.7 32 1.2 82% @ 0.25c
51 0.33 >1000 18 86 2.2 45% @ 0.1c
53 6.9 >1000 220 45 6.3 2.2
a Displacement of [33P]-labeled sphingosine-1-phosphate (S1P) by test
compounds from human S1P receptors expressed on CHO cell
membranes. Data are reported as mean for n = 3 determinations. SD
were generally ±20% of the average. See Ref. 2 for assay protocol.b See Ref. 6 for assay protocol.c Percentage decrease of peripheral blood lymphocyte counts in test
animals at the dose indicated (n = 3) versus control.
Table 1. Inhibition (IC50, nM) of [33P]-S1P binding to S1P receptorsa
by conformationally constrained analogs of 3
Compound S1P1 S1P2 S1P3 S1P4 S1P5
2 0.28 1100 6.3 15 0.77
3 3.7 580 3.6 140 13
4 16 2200 9.8 –– 24
8 1100 >1000 1200 >10000 680
12 200 >1000 410 >10000 230
16 89 >1000 190 870 660
20 50 >1000 17 150 40
23a 49 >1000 19 920 34
23b 220 >1000 51 >10000 270
26-cis 16 250 8.2 310 15
26-trans 4.9 760 7.0 180 61
29 6.9 330 5.2 120 17
33 260 >1000 220 >10000 >1000
37 360 >1000 370 6300 >1000
40a 82 >1000 30 760 130
40b-cis 23 >1000 27 2000 110
40b-trans 3.1 320 3.1 260 8.2
a Displacement of [33P]-labeled sphingosine-1-phosphate (S1P) by test
compounds from human S1P receptors expressed on CHO cell
membranes. Data are reported as mean for n = 3 determinations. SD
were generally ±20% of the average. See Ref. 2 for assay protocol.
L. Yan et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4861–4866 4865
effect had previously been seen on going from 3 to 5.5
Selecting against S1P3 has been reported to be desirabledue to the cardiovascular pharmacology associated withthis receptor.20 Cyclohexane 51 was found to be the bestof these analogs in this regard being 50-fold selective forS1P1 over S1P3. Pyrrolidine 53 showed almost 10-foldhigher affinity for S1P1 than 23a with 30-fold selectivityof S1P1 over S1P3.
The lowering of circulating lymphocytes appears to cor-relate with the immunosuppressive activity of S1P recep-tor agonists and appears to be a reasonable surrogatemarker of efficacy.6 Pyrrolidines 48-cis and 48-transwere found to induce a maximal peripheral loweringof lymphocytes in the mouse 3h after the administrationof a 0.25mg/kg iv dose while cyclohexane 51 induced a45% lowering of circulating lymphocytes after a0.1mpk iv dose. These compounds were all found tobe acutely toxic at higher doses, which is consistent withwhat has been previously reported for potent S1P3 agon-
ists.20a This precluded the determination of ED50 valuesfor these compounds. Pyrrolidine 53 was determined tohave an ED50 value of 2.2mg/kg iv in this assay. Noattempts were made to administer any of thesecompounds orally after it was determined that the max-imum plasma concentrations in the rat after a 2mg/kgpo dose of 48-cis were found to be less than 10ng/mLat all time points.
In conclusion, conformationally constrained 3-(N-alkyl-amino)propylphosphonic acids were systematically syn-thesized and evaluated as S1P receptor agonists, whichled to the identification of several suitable scaffolds forfurther investigations. The proper incorporation of aphenyl ring into the long alkyl chains of these com-pounds significantly enhanced their binding affinitiesand some of these new compounds were shown to in-duce a lowering of peripheral lymphocytes in the mouse.While none of the constrained compounds preparedhere had improved selectivity for S1P1 over S1P3 (orother S1P receptor subtypes) as compared to acycliccompounds such as 3 or 4, they do provide a set of novelstructure classes of S1P1 receptor agonists. Further elab-oration of these leads with the objective of identifyingpotent, selective, and orally bioavailable S1P receptoragonists is currently underway and will be reported inthe future.
References and notes
1. (a) Budde, K.; Schmouder, R. L.; Brunkhorst, R.;Nashan, B.; Lucker, P. W.; Mayer, T.; Choudhury, S.;Skerjanec, A.; Kraus, G.; Neumayer, H. H. J. Am. Soc.Nephrol. 2002, 13, 1073–1083; (b) Budde, K.; Schmouder,R. L.; Nashan, B.; Brunkhorst, R.; Lucker, P. W.; Mayer,T.; Brookman, L.; Nedelman, J.; Skerjanec, A.; Bohler, T.;Neumayer, H.-H. Am. J. Transplant. 2003, 3, 846–854; (c)Kahan, B. D.; Karlix, J. L.; Ferguson, R. M.; Leichtman,A. B.; Mulgaonkar, S.; Gonwa, T. A.; Skerjanec, A.;Schmouder, R. L.; Chodoff, L. Transplantation 2003, 7,1079–1084; (d) Ebeling, T.; Fishman, M. Novartis� 2003�R&D Day�, 19 November 2003.
2. Mandala, S.; Hajdu, R.; Bergstrom, J.; Quackenbush, E.;Xie, J.; Milligan, J.; Thornton, R.; Shei, G. J.; Card, D.;Keohane, C.; Rosenbach, M.; Hale, J.; Lynch, C. L.;Rupprecht, K.; Parsons, W.; Rosen, H. Science 2002, 296,346–349.
3. (a) Brinkmann, V.; Davis, M. D.; Heise, C. E.; Albert, R.;Cottens, S.; Hof, R.; Bruns, C.; Prieschl, E.; Baumruker,T.; Hiestand, P.; Foster, C. A.; Zollinger, M.; Lynch, K.R. J. Biol. Chem. 2002, 277, 21453–21457; (b) Billich, A.;Bornancin, F.; Devay, P.; Mechtcheriakova, D.; Urtz, N.;Baumruker, T. J. Biol. Chem. 2003, 278, 47408–47415.
4. (a) Matloubian, M.; Lo, C. G.; Cinamon, G.; Lesneski, M.J.; Xu, Y.; Brinkmann, V.; Allende, M.; Proia, R. L.;Cyster, J. G. Nature 2004, 427, 355–360; (b) Allende, M.L.; Dreier, J. L.; Mandala, S.; Proia, R. L. J. Biol. Chem.2004, 279, 15396–15401.
5. Hale, J. J.; Doherty, G.; Toth, L.; Li, Z.; Mills, S. G.;Hajdu, R.; Keohane, C. A.; Rosenbach, M.; Milligan, J.;Shei, G.-J.; Chrebet, G.; Bergstrom, J.; Card, D.; Rosen,H.; Mandala, S. Bioorg. Med. Chem. Lett. 2004, 14,3495–3499.
6. Hale, J. J.; Neway, W.; Mills, S. G.; Hajdu, R.; Keohane,C. A.; Rosenbach, M.; Milligan, J.; Shei, G.-J.; Chrebet,
4866 L. Yan et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4861–4866
G.; Bergstrom, J.; Card, D.; Koo, G. C.; Koprak, S. L.;Jackson, J. J.; Rosen, H.; Mandala, S. Bioorg. Med. Chem.Lett. 2004, 14, 3351–3355.
7. Beak, P.; Basu, A.; Gallagher, D. J.; Park, Y. S.;Thayumanavan, S. Acc. Chem. Res. 1996, 29, 552–560.
8. Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P.Synthesis 1994, 639–666.
9. Terao, Y.; Kotaki, H.; Imai, N.; Achiwa, K. Chem.Pharm. Bull. 1985, 33, 896–898.
10. Kehler, J.; Ebert, B.; Dahl, O.; Krogsgaard-Larsen, P.J. Chem. Soc., Perkin Trans. 1998, 3241–3243.
11. In a similar series (i.e., 3-amino-3-alkylpropyl-phosphonicacids), we have shown that an alpha-hydroxyl groupexerted a substantial beneficial effect on the binding toS1P1 receptor (Ref. 6). Although such effect has not beenstudied in 3-(N-alkylamino)propylphosphonic acid series,it is conceivably unlikely that an alpha-hydroxyl groupwill exert a substantial adverse effect on the binding.
12. Wilkinson, T. J.; Stehle, N. W.; Beak, P. Org. Lett. 2000,2, 155–158.
13. Beak, P.; Lee, W. K. J. Org. Chem. 1993, 58, 1109–1117.14. Although the length of the N-alkyl side chain is essential
for the binding to the receptor in the 3-(N-alkylamino)prop-ylphosphonic acid series, there is a range of the side chain
length where analogs have similar binding potency (Ref.5). It has been shown that C13, C14, and C15 side chaingave compounds having IC50 value within a deviation of10%.
15. Comins, D. L.; Brown, J. D. Tetrahedron Lett. 1986, 27,4549–4552.
16. Li, Z.; Racha, S.; Dan, L.; El-Subbagh, H.; Abushanab, E.J. Org. Chem. 1993, 58, 5779–5783.
17. Mori, I.; Kimura, Y.; Nakano, T.; Matsunaga, S-i;Iwasaki, G.; Ogawa, A.; Hayakawa, K. Tetrahedron Lett.1997, 38, 3543–3546.
18. Nagasaka, T.; Tsukada, A.; Hamaguchi, F. Heterocycles1986, 24, 2015–2022.
19. Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., PerkinTrans. 1, 1975, 1574–1585.
20. (a) Forrest, M.; Sun, S.-Y.; Hajdu, R.; Bergstrom, J.;Card, D.; Doherty, G.; Hale, J.; Keohane, C. A.; Meyers,C.; Milligan, J.; Mills, S.; Nomura, N.; Rosen, H.;Rosenbach, M.; Shei, G.-J.; Singer, I. I.; Tian, M.; West,S.; White, V.; Xie, J.; Proia, R. L.; Mandala, S. J. Pharm.Exp. Therap. 2004, 309, 758–768; (b) Sanna, M. G.; Liao,J.; Jo, E.; Alfonso, C.; Ahn, M.-Y.; Peterson, M. S.;Webb, B.; Lefebvre, S.; Chun, J.; Gray, N.; Rosen, H.J. Biol. Chem. 2004, 279, 13839–13848.